Watros appeared as Erin Fitzpatrick from Santa Maria California on Titus from 2000 to 2002 and gained recognition as a comedic actress, playing the real-life fiancée of the title character. According to the DVD commentary, Erin was originally supposed to be more like Tommy in the series (worrisome, neurotic), and Tommy was supposed to be more like how Erin was (strong, supportive). The characters' personality changes were made a week before the pilot was shot. After Titus was canceled, she took on the role of Kellie Newmark on The Drew Carey Show, as a replacement for the departure of Christa Miller. Watros played the role from 2002 to 2004.

From 2005 to 2006, Watros was a cast member on the ABC series Lost, playing psychologistLibby, a member of the "Tailies", a group of survivors of the plane crash who were in the tail section of the plane (and not seen during Season One). She was a romantic interest to Hurley and was very mysterious showing up in flashbacks. In the episode "Two for the Road", Libby was shot and killed by Michael Dawson. Libby briefly reappeared in the 2008 episode "Meet Kevin Johnson". She returned in 2010 in the episode "Everybody Loves Hugo" in the final season of Lost, in which she played a large part in the story. In addition, she appeared in the season finale, albeit without speaking lines.

After her departure from Lost in 2006, Watros filmed a pilot for a show titled My Ex-Life for CBS. She was slated to play the ex-wife of a character played by Tom Cavanagh. However, the pilot was not chosen by CBS.[1] Watros was also the lead in the 2007 CBS television pilot for The Rich Inner Life of Penelope Cloud, a comedy about a former literary genius who, after an awakening, decides to pursue optimism instead of cynicism.

In 2009, Watros filmed a pilot for Valley Girls, a spin-off of the CW series Gossip Girl set in the 1980s, in which she played CeCe Rhodes, the socialite ex-wife of Rick Rhodes, and mother of the series' protagonists.

Watros has been married to Curtis Gilliland since 1996. They have twin daughters, born in 2001.[3] Watros and her Lost co-star Michelle Rodriguez were each arrested on the morning of December 1, 2005, in Kailua, Hawaii, where Lost was filmed.[4] Police said both women failed field sobriety tests and were released on $500 bail each.[5]